Abstract

Background:

BRCA1 is required for proper function of the homologous recombination (HR)-mediated DNA repair pathway. BRCA1-deficiency results in genomic instability and BRCA1 mutated tumors have a specific pattern of genomic alterations. The same genomic changes can be observed in patients with BRCA1-gene methylation and in some other triple-negative patients. Using these specific alterations, a BRCA1-like classifier was developed to distinguish between BRCA1-like and breast cancers without BRCA1 deficiency (sporadic-like) (1,2).

Methods:

135 triple negative breast cancer samples with long-term follow-up were collected within the EU FP7 RATHER project. All samples were processed following one standard operating protocol to isolate RNA. We determined BRCA1 mutation and promoter methylation by next generation sequencing and multiplex ligation-dependent probe amplification (MLPA) and BRCA1-like classification by MLPA . Using full-genome expression data (Agilent) and a classification model of Linear Diagonal Discriminant Analysis (LDDA), we developed a 77-gene signature that identifies patients with a BRCA1-like status.

Results:

In the cohort of 135 TN breast cancers, 42% were classified as BRCA1-like by MLPA. Of these, 11.5% were BRCA1 mutated. Multivariate survival analysis shows that patients with a BRCA1-like tumor have a significantly worse prognosis (HR = 3.318, p = 0.012, CI = 1.299–8.475). We have integrated BRCA1-like status and BRCA1 mutation data with full genome expression data and found that the most differentially expressed genes between BRCA1-like and sporadic-like tumors were related to cell death and survival and DNA replication, recombination and repair. We have developed a gene expression signature to identify BRCA1-like patients and validated the signature in an independent test set of 53 samples showing sensitivity of 0.92 and specificity of 0.61 to distinguish BRCA1-like patients from Sporadic-like patients (BRCAness).

Conclusions:

Patients with tumors which have DNA damage repair deficiencies may be more susceptible to specific treatments such as PARP inhibitors. The development of a reliable diagnostic test might help to identify these patients in future clinical trials. 1.Wessels et al . Cancer Res 2002. 2.Vollebergh et al. Ann. Oncol. 2011.

Disclosure:

I.M. Simon, J. Peeters and R. Bernards: Employee of Agendia. All other authors have declared no conflicts of interest.